达拉非尼 T1903

Product Introduction
Bioactivity


英文名: Dabrafenib

描述: Dabrafenib (GSK2118436A) 是一种 Raf 抑制剂，抑制 C-Raf 和 B-RafV600E (IC50=5/0.6 nM)，具有 ATP 竞争性。Dabrafenib 具有抗肿瘤活性，可用于治疗 B-RafV600E 突变的黑色素瘤。

细胞实验: A375P-F11 assay: A375P cells were plated in 96-well plates by limiting dilution and single cell-derived clones were harvested and tested for sensitivity to B-Raf inhibitors. The F11 clone was selected for future studies and was named A375P-F11. Cellular pSmad Assay to Measure Anti-TGF-β Activity: Activity of compounds was tested in a mechanistic assay in HepG2 cells. Cells were seeded in 12-well plates at a density of 500,000 cells/well and allowed to adhere overnight at 37℃/5% CO2. Media (BME+10% serum) was removed and compound in serum-free media was added to the cells for 45 minutes at 37℃/5% CO2. Cells were stimulated with 1 ng/ml TGF-β for 60 minutes. Cells were lysed in buffer (25 mM Tris-HCl ph: 7.5, 2 mM EDTA, 2 mM EGTA,1% Triton X-100, 0.1 % SDS, 50 mM sodium-β-glycerophosphate, 2 mM sodium orthovanadate, 12.5 mM sodium pyrophosphate, protease and phosphatase inhibitor cocktails) for 30 minutes, scraped, collected, clarified by centrifugation and prepared for western blots in LDS/reducing reagent. Samples were resolved on 4-12% Bis-Tris gels, transferred to PVDF, and probed for total and phospho-Smad2 using antibodies. Gels were imaged using the odyssey blot scanner and quantified. Phospho:total Smad2 ratios were determined and the IC50 was defined as the concentration of compound which decreased the phospho:total ratio by 50% [1].

动物实验: Cells were implanted in nude mice and grown as tumor xenografts. Dosing began when tumors achieved ~150-200mm^3 volume. GSK2118436 was administered by oral gavage at a dose volume of 0.2 mL/20 gram body weight in 0.5% hydroxypropylmethylcellulose and 0.2% Tween-80 in distilled water pH 8.0. Dosing was daily for duration stipulated. Results are reported as mean tumor volume for n=7-8 mice/group. Tumors were measured twice weekly with Vernier calipers, and tumor volume was estimated from two-dimensional measurements using a prolate ellipsoid equation (Tumor volume mm^3 = (length x width^2) x 0.5). Complete tumor regression was defined as a >93% decrease in an individual tumor volume for at least 1 week [1].

体外活性: 方法：195 种肿瘤细胞用 Dabrafenib 处理 72 h，使用 CellTiter-Glo Assay 检测细胞生长。结果：编码 BRAFV600E 的 20 个细胞系中有 16 个对 Dabrafenib 敏感 (gIC50<200 nM)。其他 5 个突变 BRAF 细胞系中的 3 个对 Dabrafenib 敏感 (gIC50<30nM)，包括 WM-115(BRAFV600D) 和 YUMAC(BRAFV600K)。152 个 RAS/RAF 野生型中的133个和所有 18 个突变 RAS 细胞系对 Dabrafenib 不敏感 (gIC50>10µM)。[1]方法：黑色素瘤细胞株 LCP(BRAFV600R)、WM266 (BRAFV600D) 和 M257 (BRAFWT) 用 Dabrafenib (3-100 nM) 处理 72 h，使用 Western Blot 检测靶点蛋白表达水平。结果：与具有野生型 BRAF 的对照细胞相比，具有 BRAFV600D/R 突变的细胞系对磷酸化 ERK 表现出更快更强的抑制作用。[2]

体内活性: 方法：为检测体内抗肿瘤活性，将 Dabrafenib (3-100 mg/kg，0.5% hydroxypropylmethylcellulose+0.2% Tween 80 in pH 8.0 distilled water) 灌胃给药给携带人结直肠癌肿瘤 Colo 205 (BRAFV600E) 的 CD1 nu/nu 小鼠，每天一次，持续十四天。结果：Dabrafenib 显示出剂量依赖性的肿瘤生长抑制作用，8 只小鼠中有 4 只在 100 mg/kg 剂量下显示出部分消退。[1]方法：为检测体内抗肿瘤活性，将 Dabrafenib (0.1-100 mg/kg，0.5% hydroxypropylmethylcellulose+0.2% Tween 80 in pH 8.0 distilled water) 灌胃给药给携带人恶性黑色素瘤 A375P F11 (BRAFV600E) 的 CD1 nu/nu 小鼠，每天一次，持续十四天。结果：Dabrafenib 可显著减少携带 B-RafV600E 人类黑色素瘤肿瘤的小鼠的肿瘤生长。100 mg/kg 组中，50% 的治疗动物观察到肿瘤完全消退。[3]

存储条件: Powder: -20°C for 3 years | In solvent: -80°C for 1 year

溶解度: 5% DMSO+95% Saline : 1.4 mg/mL (2.69 mM, suspension)
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 55 mg/mL (105.86 mM)


关键字: GSK-2118436 | inhibit | Dabrafenib | Raf kinases | GSK 2118436 | Inhibitor | Raf

相关产品: SOS1-IN-11 | LY2452473 | GSK1904529A | 6H05 | GSK2008607 | Kobe0065 | B-Raf IN 2 | LUT014 | AZ 628 | Sulindac sulfide

相关库: Drug Repurposing Compound Library | FDA-Approved Kinase Inhibitor Library | Anti-Cancer Drug Library | Anti-Cancer Clinical Compound Library | Inhibitor Library | Kinase Inhibitor Library | Anti-Cancer Active Compound Library | Tyrosine Kinase Inhibitor Library | Anti-Cancer Approved Drug Library | EMA Approved Drug Library

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注：该产品未在中华人民共和国食品药品监督管理部门申请医疗器械注册和备案，不可用于临床诊断或治疗等相关用途